Systems and methods for the treatment of pelvic disorders including magnetic particulates

ABSTRACT

Systems and methods of localizing or delivery cells, biologics and/or drugs to a specific target area to treat pelvic health disorders are provided. A treatment composition including cells, biologics and/or drugs are associated with magnetic particulates, and the positioning of these materials is facilitated through use of a magnetic field-generating device that is configured to be placed on or into a pelvic anatomical structure. Certain embodiments directed to the treatment of ED in male patients can include a cell based therapy system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of, and claims priority to, U.S.patent application Ser. No. 13/205,039, filed on Aug. 8, 2011, now U.S.Pat. No. 9,669,200, entitled “SYSTEMS AND METHODS FOR THE TREATMENT OFPELVIC DISORDERS INCLUDING MAGNETIC PARTICULATES”, which, in turn,claims priority to U.S. Patent Application No. 61/371,232, filed on Aug.6, 2010, and U.S. Patent Application No. 61/371,609, filed on Aug. 6,2010, the disclosures of which are incorporated by reference herein intheir entirety.

FIELD OF THE INVENTION

The present invention relates generally to targeted treatment deliveryand, more particularly, to targeted introduction, positioning andcontrol of cells, drugs or other agents treating various pelvic healthissues or disorders.

BACKGROUND OF THE INVENTION

Erectile dysfunction (ED) is believed to affect more than ninety millionmen in the United States and Europe, with seventeen million presentingwith severe conditions that greatly interfere with the ability toinitiate and maintain erections. ED may arise from a number of causes.Age brings on a lack of arterial elasticity in vessels supplying bloodto erectile tissues. Damage to nerves necessary for initiating andsustaining erections brought on by chronic conditions (such as diabetes)or by injury can lead to dysfunction. A significant cause of nervedamage comes from injury that occurs during prostate surgeries,especially radical prostatectomies. Although new surgical procedureshave been introduced that conserve the nerves in this region, a majorityof men who undergo such procedures can still expect some degree of postoperative ED.

A number of oral medications for treating ED have entered themarketplace in recent years, including VIAGRA, CIALIS and LEVITRA. Thesemedications all provide significant relief to a large segment of menwith ED. However, they each require that the medication be taken inadvance of initiation of sexual activity and their effects may bedelayed if ingested with food. Further, the effectiveness of such drugscan vary greatly from patient to patient, and is even ineffective in alarge cross-section of patients.

Various treatments have also been tried in connection with ED, includingadministration of Prostaglandin E1 by injection into the cavernosum ofthe penis, by administration of a suppository into the urethra and bytopical administration. These approaches allow for less advancepreparation, but are neither consistently effective nor desirableapplications across patient populations, especially radicalprostatectomy patients.

Surgical interventions are also available for addressing ED, especiallywhere medications are ineffective or contraindicated. Penile implants ofmany different configurations are used to provide support for anerection. These implants are effective in restoring patient sexualsatisfaction. Increasingly, these implants have been engineered to becompletely concealed within the patient. However, implants may fail overtime and replacement or total removal may be required potentiallyleaving the patient with no relief at all. In addition, penile implantsare an end stage treatment, and it is often desirable to providetreatment earlier in the disease state. Thus, there is a desire toobtain a minimally invasive yet effective and durable solution to treatED that can be used with minimal to no side effects.

In addition to ED, there is a need for alternative yet effectivesolutions to treat other damaged or defective tissues within the pelvicregion of a patient (male or female), including conditions such as maleand female fecal and urinary incontinence, bladder pain, vaginalprolapse, and overall uterine health.

SUMMARY OF THE INVENTION

Various embodiments of the present invention can be utilized to localizeor deliver cells, biologics and/or drugs to a specific target area totreat pelvic health disorders. The delivery mechanism can be directed tocells associated with magnetic particulates, or magnetic particulatessuch as magnetic microparticles (MMPs) coated with biologics or drugs,that are adapted to treat a pelvic disorders or conditions.

Treatment applications can include ED, urinary and fecal incontinence,prolapse, fistulas, fibroids, abnormal uterine bleeding, prostatichyperplasia, cancer, and the like.

One embodiment of the invention provides a system for the treatment of apelvic disorder. The system includes magnetic particulates which areeither (i) physically associated with a cell population (ii) orphysically associated with a biologic or drug, or both (i) and (ii),which are configured for injection into a pelvic tissue. The system alsoincludes a device configured for placement on or into, or configured tobe associated with, a pelvic anatomical structure selected from thegroup consisting of the urethra, the penis, the vagina, and the rectum.The device comprises a member capable of providing a magnetic fieldwhich influences the positioning of the magnetic particulates within thepelvic tissue.

In exemplary embodiments, the magnetic-field generating device isassociated with permanent magnets and/or electromagnets, and the deviceis configured for used on or in the urethra, the penis, the vagina, orthe rectum.

A related embodiment of the invention provides a method for thetreatment of a pelvic disorder. The method comprises a step ofdelivering a treatment composition to pelvic tissue, wherein thecomposition comprises magnetic particulates, and in the composition themagnetic particulates are either (i) physically associated with a cellpopulation (ii) or physically associated with a biologic or drug, orboth (i) and (ii). The method also comprises a step of placing a devicein proximity to tissue where magnetic particulates are delivered orintended to be delivered, wherein the device is configured for placementon or into, or configured to be associated with, a pelvic anatomicalstructure selected from the group consisting of the urethra, the penis,the vagina, and the rectum, wherein the device comprises a member thatprovides a magnetic field and affects positioning of the magneticparticulates within the pelvic tissue.

The system and method of the invention can further include an injectiondevice capable of injecting the cell population comprising the magneticparticulates or a biologic or drug associated with the magneticparticulates into pelvic tissue.

Other embodiments of the invention that are directed to the treatment ofED in male patients can include a penis lifter and mixer system havingan external device configured to manipulate the penis and move cells,biologics, or drugs within the vascular spaces to tissue in need ofregeneration. For instance, the device can include a construction bandplaced in or on the penis to provide a gentle but effective rotationalforce on the dorsal surface of the penis to allow a cell solution tomove through the tissue from base to tip and back again in a controlledmanner. This will, in turn, allow the cell solution to fill all of thespaces to give the cells an opportunity to take hold of the local tissueto advance regenerative opportunities.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a condom on a penis with permanentmagnets attached to the condom around its circumference.

FIG. 2 is a schematic illustration of a condom on a penis with permanentmagnets attached to the condom on a strip along the condom length.

FIG. 3 is a schematic illustration of a cross section of a penis withcondom showing the location of magnets equally spaced around thecircumference of the condom.

FIG. 4 is a schematic illustration of a cross section of a penis withcondom showing the location of magnets unequally spaced around thecircumference of the condom.

FIG. 5a is a schematic illustration of a cross section of a penis withcondom showing the location of injection of a therapeutic compositioninto the corpus cavernosum.

FIG. 5b is a schematic illustration of a cross section of a penis withcondom with magnets unequally spaced around the circumference of thecondom, with movement of the condom in clockwise and counterclockwisedirections.

FIG. 6 is a schematic illustration of a condom on a penis with a smallelectromagnet coil attached to the condom.

FIG. 7 is a schematic illustration of a condom on a penis with a wireattached to and wrapped helically around the condom to form anelectromagnet.

FIG. 8 is a schematic illustration of a magnetic penis ring on a penis.

FIG. 9a is a schematic illustration of a penis roller device.

FIG. 9b is a schematic illustration of a penis roller device with penis.

FIG. 9c is a schematic illustration of a penis roller device.

DETAILED DESCRIPTION

The embodiments of the present invention described herein are notintended to be exhaustive or to limit the invention to the precise formsdisclosed in the following detailed description. Rather, the embodimentsare chosen and described so that others skilled in the art canappreciate and understand the principles and practices of the presentinvention.

All publications and patents mentioned herein are hereby incorporated byreference. The publications and patents disclosed herein are providedsolely for their disclosure. Nothing herein is to be construed as anadmission that the inventors are not entitled to antedate anypublication and/or patent, including any publication and/or patent citedherein.

Various embodiments of a localized agent or cell delivery system andmethods are provided. A variety or combination of cells, biologicsand/or drugs can be delivered to specific target areas of tissue regionsto treat disorders such as ED, urinary and fecal incontinence, bladderpain, vaginal prolapse, fistulas, fibroids, uterine bleeding, cancer andother pelvic health issues. The cells, biologics and/or drugs areassociated with magnetic particulates. A part of the system and methodis a device that provides a magnetic field which influences thepositioning of the magnetic particulates and associated cells,biologics, or drugs within the pelvic tissue. The systems can optionallyinclude other devices adapted to facilitate the delivery or introductionof the cells, biologics and/or drugs, such as injection devices ordevices that mechanically promote the distribution of the cells,biologics and/or drugs in the tissue. These devices can be constructedof materials such as polymers, metals, and other like materialscompatible for use in treating the disclosed and contemplated pelvicdisorders or conditions.

Magnetic particulates can be associated with the cells, biologics and/ordrugs so that when delivered to a target tissue in the body and affectedby the magnetic field, the magnetic particulates direct positioning ofthe injected material within the tissue. Magnetic particulates can beassociated by a physical or chemical association between the magneticparticulates and the cells, biologics and/or drugs, or by placing themagnetic particulates, for example, within cells.

As used herein, “magnetic particulates” include any type of spherical ornon-spherical (irregular shaped) particle made of or including magneticmaterial. Magnetic material suitable for use in the body includesmagnetic iron oxides like Fe₃O₄ (magnetite) and γ-Fe₂O₃ (maghemite) Themagnetic particulates associated with the cells, biologics and/or drugsare considered “biocompatible” as they can be used in the body withoutpresenting toxicity concerns or eliciting a negative cellular response.Iron oxide particulates have been used in the body and can be excretedvia the liver.

Magnetic particulates can be described by geometric as well magneticproperties, if desired. Geometric parameters include, for example, size,shape, bond lengths, composition, and crystal structure, whereasmagnetic parameters include, for example, magnetic moments, saturationmagnetization, and remnant magnetization. Techniques such as x-raydiffraction (XRD) and transmission electron microscopy can be used forgeometric characterization, and magnetometry can be used for magneticcharacterization of the magnetic particulates.

Magnetic particulates include nanoparticles and microparticles havingmagnetic properties. For purposes of discussion relating to size,magnetic nanoparticles have a size of 999 nm or less, such as in therange of about 10 nm to about 500 nm. Magnetic microparticles arecharacterized as having a size of 1 μm or greater, such as in the rangeof 1 μm to about 100 or 1 μm to about 20 μm.

In some cases, magnetic particulates are prepared predominantly(e.g., >95%) or entirely from magnetic material, such as magnetic ironoxides. These preparations are typically in the nanoparticulate sizerange. Various techniques are available for the synthesis of magneticnanoparticles including: reduction of metal-salts, gas-phase reductionof metal complexes, micro-emulsion, and thermal decomposition ofmetal-carbonyl complexes. Synthesis techniques can include use ofsurfactants to control particle size, as well as use of acidic materialsuch as citric acid or oleic acid to stabilize the particles. Particlescan be coated, such as with a polymer or a surfactant to preventaggregation of the magnetic particulates. Exemplary materials thatprevent particle aggregation or precipitation are dextran andcarboxydextran. Magnetic nanoparticulates are available from, forexample, Sigma-Aldrich, as well as those sold under the tradenameFerucarbotran™ (Resovist™; Bayer Schering Pharma AG, Germany). Magneticnanoparticles can be incorporated into larger structures, such as cells,microvessicles, or microparticles, or can be directly associated withdrags or biologics.

Some embodiments of the invention utilize magnetic microparticulates,and in some preparations the magnetic material may represent a portionof the overall material of the microparticle, with the remaining portionbeing a non-magnetic material, such as a polymeric material, a drug, orbiologic, or combinations thereof. However, the presence of the magneticmaterial in the particle still provides the microparticle with magneticproperties.

In some aspects, the system and methods utilize magnetic polymericmicroparticles. Polymers suitable for polymeric microparticles includebiocompatible non-degradable or degradable polymers. Exemplarybiodegradable polymers include natural polymers such as starch, dextran,and albumin, and synthetic degradable polymers such as polyesters, likepolylactide and polyglycolide, and polyamides.

Magnetic polymeric microparticles may be prepared by incorporatingmagnetic oxides into polymeric spheres. Polymeric spheres can beprepared with magnetic nanoparticles entrapped or impregnated in thesphere (for example, see, Oh, I. J., et al. (1993) Arch. Pharm. Res.16:312-317). Entrapment methods can produce particles with a magneticcore composed of dispersed nanoparticle clusters (5-50 nm per particle)or nanoparticles surrounded by a polymer matrix. Magnetic nanoparticlescan be suspended in the polymeric solution prior to cross-linking orsolvent evaporation. The impregnation method involves the incorporationof magnetic oxide particles within the pores of preformed microsphereswith a homogenous precipitate of magnetic oxide particles within thewhole particle (for example, see, Schutt, et al. (1999) ArtificialOrgans 23:98-103).

In some aspects, a drug or biologic is used in the microparticlepreparation process and incorporated into the microparticle along withthe magnetic particulates.

Some embodiments of the invention utilize magnetic particulates havingsurface chemistries useful for interaction with a target moiety, such asa drug, a biologic, or a cell. In some cases, these types of magneticparticulates are coated with a material, such as a polymer, or made froma polymeric material, that provides a chemistry on the particulatesurface that is useful for bonding or association with a target moiety.For example, magnetic polymeric microparticles can coated witholigomeric compounds, forming a thin shell to which specific ligands canbe linked. Some biologics, like antibodies, can be directly adsorbed onthe particle surface as a result of hydrophobic interactions, or theycan be covalently coupled by first activating a chemical group on thesurface of the particle. Surface functionalized magnetic microparticlescan further be associated with a drug, cell, or biologic throughchemical reaction or interaction between the surface chemistry on themicroparticles and a portion of the drug, cell, or biologic. Exemplarysurface chemistries include, but are not limited to, carboxyl,streptavidin, and coordination complexes that allow for multivalentbinding with a suitable target moiety. Magnetic polymeric microparticleshaving surface chemistries suitable for bonding to various drugs,biologics, and cells are commercially available from, for example, BangsLaboratories (Fishers, Ind.).

Alternatively, drugs or biologics useful for treatment pelvic tissueconditions can be incorporated into a microcapsule along with magneticnanoparticles. An exemplary preparation is an albumin microcapsules(0.2-2.0 μm) containing both Fe₃O₄ particles (10-20 nm) andchemotherapeutic agents (for example, see, Arshady, et al. (1990)Journal of Controlled Release 14:111-131).

In some embodiments, the magnetic particulate is associated with a drugthat is useful for the prevention or treatment of a condition

Classes of drugs for treatment of pelvic tissue related conditionsinclude but are not limited to: analgesics, anesthetics, antibiotics,anti-cancer substances, anti-cholinergics, anti-coagulants,anti-inflammatory agents (such as NSAIDs), anti metabolites,antimitotics, antioxidizing agents, antiproliferatives, includingantiangiogenesis agents, antiseptics, antiviral agents, cell responsemodifiers, chemotherapeutic agents, extracellular matrix components,growth hormone antagonists, immunosuppressive agents, musclecontractants, polynucleotides and derivatives thereof, opioids,prostaglandins, steroids, thrombolytic agents, vasodilators, andvasospasm inhibitors.

Drugs that can be associated with the magnetic particulate and usefulfor the treatment of erectile dysfunction include phosphodiesterase type5 inhibitors, such as sildenafil, avanafil, lodenafil, mirodenafil,tadalafil, and varendenafil; prostaglandin E₁. (PGE1; alprostadil);papaverine; and phentolamine. Biologics that can be associated with themagnetic particulate and useful for the treatment of erectiledysfunction include gene therapy agents, such as nucleic acids encodingfor potassium channel proteins, such as the large conductance, calciumchannel protein Maxi-K (Slo) (Christ et al. (2009) European Urology 56:1055-1066).

Drugs for proposed treatment of urinary incontinence includetachykinin-receptor (NK) antagonist TAK637 (NK-1 receptor antagonist);oxybutynin; and resiniferitoxin

A drug useful for the treatment of fistula (in women with Crohn'sdisease) is infliximab (Remicade).

Chemotherapeutic drugs for the treatment of malignant growths, such asprostate cancer, include vinblastine, mitoxantrone, cisplatin,methotrexate, carboplatin, etoposide, mitomycin-C, 5-fluorouracil,vincristine, bleomycin and ifosfamide.

After the treatment composition has been injected into pelvic tissue andthe drug has been positioned as desired via use of the magnetic fieldgenerating device, the drug can be become unassociated with the magneticparticulate to provide a pharmacological effect.

In some aspects of the invention cells that are associated with magneticparticulates are used for treatment. The magnetic particulates can beassociated with the cell by incorporating the particulate into the cell,such as by endocytosis, or by binding particulates to the outer surfaceof the cell, such as through a membrane protein interaction. Cell-basedtherapies can be useful for the reconstruction or regeneration ofdamaged or dysfunctional pelvic tissue.

In some aspects, a cell population that includes primary cells or stemcells is obtained from adipose tissue and associated with the magneticparticulates for the treatment of a pelvic condition. Stem cells can beobtained from a patient using procedures such as surgical or suctionlipectomy. Cells obtained by lipectomy can be associated with themagnetic particulates and then reintroduced into the same patient,thereby providing an autologous source of cells. Adipose tissue can beprocessed to separate the adipose-derived stem cells from the othermaterial including other cellular and non-cellular material in theadipose tissue. Preparation methods can include steps of washing thetissue, treating the tissue with collagenase or trypsin, or optionallywith mechanical agitation. Liposomes, which are generally aggregated,can be separated from free stromal cells which include the stem cellsand other cells such as red blood cells endothelial cells, andfibroblast cells, by centrifugation. Erythrocytes can be lysed from thesuspended pellet and the remaining cells can be filtered or centrifuged.Optionally, cells may be separated by cell sorting or separatedimmunohistochemically. Methods for the preparation of adipose-derivedstem cells are described in commonly assigned application number. WO2009/120879.

Prior to use in the system or methods of the invention, stem cells mayoptionally be cultured and, if desired, assayed for number and viabilityto assess the yield.

Various techniques can be used to incorporate magnetic nanoparticlesinto cells, such as by nanomagnetic transfection, specific targeting andendocytosis of nanoparticles through the use of transferrin receptors,magnetodendrimers, or by electroporation.

For nanomagnetic transfection a magnetic force is applied beneath thecells to be transfected. This draws the magnetic nanoparticle onto cellson the bottom of the multi-well plate or cell culture flask used. Themagnetic particulate is delivered into, target cells, generally viaendocytosis. This leads to rapid and efficient transfection withoutdisturbing membrane architecture and without causing chromosomal damageor leaving holes in cell membranes. (see, for example, Dobson, J., etal. (2008) Eur. Cells & Mater. 16: 48).

Surface coated magnetic nanoparticles, such as carboxydextran,poly-L-lysine, D-mannose, or poly(N,N-dimethylacrylamide) may beattached to the outer surface of cells. Ferucarbotran™ is a commerciallyavailable preparation of carboxydextran-coated super paramagnetic ironoxide particles.

Optionally, a composition including magnetic particulate-associatedcells can include material that promotes cell survival and/orintegration into the tissue in which it has been injected into. Thematerial can be a natural material that serves as a cellular scaffoldingor extracellular matrix material.

In some aspects, a composition with cells can be mixed with mechanicallyprocessed adipose tissue. To obtain this material, lipoaspirate from apatient can be obtained and then disaggregated by mechanical force, suchas by cutting, chopping, or mincing the adipose tissue. Collagenase ortrypsin (enzymatic) digestion is not performed to maintain thescaffolding features of the adipose tissue. In some preparations, thecells are mixed with the undigested portion of the adipose tissue at aweight ratio in the range of about 1:1 to about 1:4. Methods for thepreparation of an adipose tissue-derived scaffolding for cells aredescribed in commonly assigned International ApplicationPCT/US2009/038426 (WO2009/120879).

In some embodiments, the treatment composition including magneticparticulate-associated cells further includes Platelet Rich Plasma(PRP). PRP is blood plasma enriched with platelets. Throughdegranulation of the platelets, PRP can release different cytokines thatcan stimulate healing of soft tissue. Processes for PRP preparationinclude the collection of centrifugation of whole blood which separatesPRP from platelet-poor plasma and red blood cells. In some cases, theadipose-derived stem cells are combined with PRP cell based therapy. Thehealing proteins in PRP are advantageous and can assist in making thesinusoid spaces within the cavernosum of the penis “sticky” for theattraction and retention of the treatment cells. PRP also includes manyregenerative proteins to hasten healing. Leveraging the graspingcapability of PRP following an injection of adipose derived cells servesas an optimal combination to provide not only duplicitous sources ofregenerative proteins and cytokines to improve healing, but also offersfacilitates tissue adherence. The adhesive or retention function of thePRP will assist in preventing the cells from migrating or being lostthrough vascular flow to the lungs. This improved cell retention withinthe cavernosum provides and signals vascular regeneration to treaterectile function.

In some embodiments, the treatment composition including magneticparticulate-associated cells further includes Platelet Poor Plasma(PPP). PPP is typically characterized by a very low number or platelets(<50000/uL) and a high concentration of fibrinogen. PPP can be preparedin a centrifugation process that separates it from PRP and red bloodcells. PPP can provide an autologous scaffold-like material to keepinjected cells local to the injection region to improve the regenerativepotential of the cells. PPP can be beneficial to tissue as well. The PPPcan include a porous gelatinous material to keep cells local to theinjection site, allowing the cells to stay local and thereby betterimpact the intended target tissue. PPP can allow the movement ofcytokines and other signaling molecules in and out of the tissue forregenerative mechanisms local to the injection site. The PPP and celldevices can be combined into one delivery tool.

As used herein, a “therapeutic composition” includes the magneticparticulates associated with cells, biologics, or drugs, or combinationsthereof. The composition can contain a therapeutically effective amountof cells, biologics, or drugs suitable when used in conjunction with themethods of the invention. A therapeutically effective amount refers tothat amount of cells, biologics, or drugs alone, or optionally togetherwith other substances, that produces the desired effect (such astreatment of a medical condition such as erectile dysfunction, or tissuerepair for the treatment of weakened pelvic anatomy) in a patient.During treatment, the amounts of cells, biologics, or drugs used willdepend upon such factors as the particular condition being treated, theseverity of the condition, the individual patient parameters includingage, physical condition, size and weight, the duration of the treatment,and any optional concurrent therapy, as recommended by the healthpractitioner. A physician or veterinarian of ordinary skill can readilydetermine and prescribe the effective amount of cells, biologics, ordrugs required to affect the condition.

The therapeutic composition can include one or more excipients thatimprove the stability of the composition, and/or enhance the activity ofthe biological, drug, or cellular active in the composition. Additionalexcipients can include additives or auxiliary substances such as anantioxidants, antiseptics, isotonic agents, and buffering agents.

A “subject” refers to an organism to which the system and methods of theinvention can be applied. The subject can be a human (male or female),another mammal having pelvic anatomy appropriate for application of thesystem and methods of the invention. For example, the subject can be adomesticated mammal such as a dog, cat, horse, cow, sheep, rabbit, etc.

Optionally, the system can include an injection device capable ofinjecting a therapeutic composition into pelvic tissue. Exemplaryinjection devices include needles, syringes, trocars, cannulas,catheters, tubes, and other devices having delivery capabilities. Aninjection device configured for delivery of the therapeutic compositionin a subcutaneous, intramuscular, periurethral, or intraperitonealmanner can be used.

Treatment can involve a single injection, or multiple injections oftreatment composition. If multiple injections are performed, theinjections can be performed at the same injection site, or at differentsites in the general area of treatment (e.g., multiple sites along thesurface of the penis.) One mode of injection involves advancing a needleinto tissue from an area outside the body. Another mode of injectioninvolves use of a device which is placed within the body, such as acatheter, and then from that device a needle pierces a tissue in thebody and the composition is delivered into the desired tissue location.

For example, with regards to the penis, in one mode of practice, needleinjection of the therapeutic composition from outside the body can bemade through the skin of the penis and the superficial and deep facia,and into target tissue such as the corpus cavernosum or the corpusspongiosum. In another mode of practice, needle injection of thetherapeutic composition from inside the body can be made using aurethral catheter having a needle which extends from the catheter andpierces the urethral wall and into the corpus cavernosum or the corpusspongiosum, or into the prostrate.

In some aspects, the system and methods include an injection device thatis capable of delivering the treatment composition transurethrally intoa desired target tissue. For transurethral injection, the target tissuemay be selected from corpus cavernosum, bladder, and prostrate.

One device that can be used for transurethral delivery of a therapeuticcomposition is a needless injector device. The device has a shaft thatcan be navigated through the urethra, to place the distal end of thedevice at a target location where the injection is desired. The devicecan eject fluid from at least one injection orifice located at thedistal end of the shaft. Optionally, multiple injection orifices may belocated at one or more locations along a length of or about acircumference of a shaft distal end. The fluid-based compositionpenetrates through a surface of a tissue, without the use of a needle,and into the bulk of the tissue, and dispersing as particles or dropletswithin the tissue below the tissue surface. A needleless transurethraldelivery device which can be used as a component in the system andmethods of the invention is described in commonly assigned U.S.Publication Number 2006/0129125 (Copa et al.).

Another device that can be used for transurethral delivery of atherapeutic composition is a needled injector device. The needled devicealso has a shaft that can be navigated through the urethra, to place thedistal end of the device at a target location where the injection isdesired, but the device can eject fluid from a needle located near thedistal end of the shaft. A needled transurethral delivery device whichcan be used as a component in the system and methods of the invention isdescribed in commonly assigned U.S. Publication Number 2006/0122281(Sousa Escandon et al.).

The system also includes a device that provides or generates amagnetic-field (“magnetic-field device”). The magnetic-field device canbe configured for placement on or into a pelvic anatomical structuresuch as the urethra, the penis, the vagina, and the rectum.Alternatively, the device can be configured to be associated with apelvic anatomical structure as described. In exemplary aspects, themagnetic-field device can be in the form of a male condom, a penis ring,an intravaginal device, a pessary, or a urethral catheter.

When placed on or into the anatomical structure in the pelvic area, themagnetic-field device can influence the positioning of the magneticparticulates within the pelvic tissue. The magnetic design parameters inthe magnetic-field device can be tailored to conform to a particulartreatment protocol. The magnetic-field device can be useful formaintaining the cells, biologics, or drugs at the desired treatment areaso they are not removed by fluidics of the vascular or lymphatics systemin the treatment area.

In some modes of practice, the magnetic-field device can produce theguided migration of cells, biologics and/or drugs associated with themagnetic particulates. Cells, biologics and/or drugs associated with themagnetic particulates can be acted on by magnetic fields and gradientsgenerated by the devices of the invention in order to produce thedesired motion. Magnetic fields and gradients are used to produce forcesand torques on of the magnetic particulates inside the pelvic tissue.Through control of the fields and gradients, the magnetic particulatescan be made to move through the pelvic tissue thereby carrying thecells, biologics and/or drugs with them.

As a general matter, the magnetic field generating device is associatedwith one or more series of permanent magnets, or one or moreelectromagnets. The magnet devices can include coils, magnetic nodes,sleeves, inductors, solenoids, and other like structures or componentsto facilitate the positioning of the magnetic particulates withassociated cells, biologics, or drugs within the pelvic tissue.

Permanent magnets can be made of materials such as alnico, neodymiumiron boron (NdFeB), and samarium cobalt (SmCo). Small permanent magnets,including those having dimensions less than a millimeter, arecommercially available (e.g., BM Magnetics, Leominster, Mass.) Permanentmagnets can be associated with the devices of the systems in a varietyof ways. For example, permanent magnets can be adhered to a portion ofthe device using an adhesive, can be incorporated into a plasticmaterial of the device by using the magnets along in an extrusion,lamination, or molding process; can be sintered or welded to a portionof the device, can be mechanically fastened to the device, or can beshaped to fit or interlock with a portion of the device.

In some aspects, the device includes an electromagnet, which is anon-permanent magnet in which the magnetic field is produced by the flowof an electric current conductive material, such as a coil. A currentflowing through the coil material produces a magnetic field, and thefield disappears when the current ceases. In the presence of a current,magnetic domains align with the applied field, causing an increase inthe magnetic field strength. One or more electromagnets associated withthe device can be controlled in a variety of ways to provide a magneticfield that influences positioning of the magnetic particulate-associatedcells, biologics, or drugs in the pelvic tissue for a particularcondition to be treated. For example, the magnetic field can be rapidlymanipulated over a wide range of values by controlling the strength ofthe electric current, thereby controlling the forces acting on theparticulates. The duration of an applied magnetic field can also becontrolled, thereby controlling the amount of time forces act on theparticulates. Further, in some embodiments, when more than oneelectromagnet is used with a device, the device can have an electroniccontrol to provide magnetic fields at different locations on the deviceat different times. A method using this type of control can cause themovement of particles in different directions at different times toenhance penetration and distribution of the cells, biologics, or drugsthroughout the tissue to be treated. It can also cause the particles tobe maintained within the tissues in which they were injected rather thanbeing carried off by fluidics of the body. In addition, the inventionalso contemplates use of electromagnets formed by including a permanentmagnet in an electronic circuit. In these arrangements, a magnetic fieldis present until a current is applied.

In some aspects of the invention, the magnetic particulates withassociated cells, biologics, or drugs can be retained within the peniswith the use of a proximate or external magnet device. The magneticdevice can be implemented in various configurations to promote thedesired and proximate magnetic field interaction with the magneticparticulates with associated cells, biologics, or drugs. In some modesof practice the magnetic field generating device is used for thecontrolled retention and migration prevention. Through use of thedevice, injected magnetic particulates with associated cells, biologics,or drugs are better positioned and retained at the site of the damage ordisorder.

In one aspect, the system and methods of the invention include amagnetic-field device used in conjunction with the penis. To positionand maintain the external magnets proximate to the magnetic particulateswith associated cells, biologics, or drugs, the magnets can be providedwith a cuff, a condom-like device, or other like devices adapted toengage or surround at least a portion of the penis. Exemplary devicesinclude magnetic condoms and magnetic penis rings, or other like devicesadapted to engage or surround at least a portion of the penis. Oneembodiment of the invention uses a condom that includes a permanentmagnetic material associated with the condom. The condom can formed offlexible polymeric sheath material and can have one or more permanentmagnets) associated with the polymeric sheath material. Polymeric sheathmaterials can be selected from those typically used to make condoms,such as, polyvinyl chloride (PVC) or latex. The one or more magnets canbe associated with the sheath at one or more points along the sheathlength. Since the sheath can be rotated on the penis during a step oftreatment, the positioning of the magnet(s) with regard to thecircumference of the sheath may not be critical for some embodiments.

In one embodiment as shown in FIG. 1, the partial condom 10 has a seriesof permanent magnets (12 a, 12 b, 12 c, 12 d, 12 e, 12 f, etc.) arrangedaround the circumference of the condom. The magnets can be placed aroundthe circumference along the entire length of the condom, or can beplaced at positions near the proximal end, distal end, or the center, orcombinations thereof, along the length of the condom. FIG. 1 shows themagnets being placed near the proximal end of the condom. The number andsize of the permanent magnets can be chosen based on the desiredstrength of the magnetic field to be associated with the condom.Exemplary designs include a series of magnets arranged around thecircumference at any particular location along the condom length. Toconstruct the magnetic condom, an adhesive can be used to glue thepermanent magnets to the latex sheath. The partial condom shown in FIG.1 has an open distal end, but can be provided with a closed distal endto cover the glans penis, similar to traditional condoms.

Another embodiment, shown in FIG. 2, uses a series of permanent magnetsarranged along the length of the sheath. For example, magnetic condom 20includes a series of permanent magnets (22 a, 22 b, 22 c, 22 d, 22 e,etc.) that are associated with the sheath in a linear configuration(running along strip 24) from the proximal to distal end of the sheath.In other embodiments, the magnetic condom has more than one strip ofmagnets located around its circumference. For example, the magneticcondom can include two, three, four, or more than four strips of magnetsaround its circumference, each strips spaced equally around thecircumference, or not spaced equally around the circumference. Forexample, FIG. 3 is a cross-sectional view of the penis 30 (showinganatomical structures of the corpus cavernosum 31, corpus spongiosum 32,and urethra 33) with condom 34 having three strips of magnets (35, 36,and 37) spaced equally around the circumference of the condom. Inanother embodiment, FIG. 4 is a cross-sectional view of the penis 40 andcondom 44 showing three strips of magnets (45, 46, and 47) spacedunequally around the circumference of the condom.

Use of a magnetic condom in conjunction with the methods of theinvention are exemplified as follows. A composition that includesmagnetic particulate-associated cells, biologics, or drugs can beintroduced into the corpus cavernosum by a suitable technique such asneedle injection. Injection of the composition can be performed at oneor more locations along the length and/or circumference of the penis sothat a desired amount of composition becomes present at the tissue siteswithin the penis. Multiple injections are made into the corpuscavernosum, if desired. In some modes of practice a series of injectionsmay result in a total volume of composition being injected into thepenis in the microliter to milliliter range. Injections can be performedprior to placement of the magnetic condom on the penis, or injectionscan be made after the condom is in place. If injections are made afterthe condom is in place, the condom can optionally include one or moreaperture(s) for the needle to pass through so the sheath does not needto be penetrated with the needle. The one or more apertures may alsoserve as a guide to for injection sites into the penis.

In some modes of practice, one or more injections of a treatmentcomposition can be made into tissue of the penis adjacent to placementof magnetic strips when the magnetic condom is situated on the penis.For example, with reference to FIG. 5a , arrows 57 a and 57 b representinjection locations of the composition on the right and left sides ofthe penis 50, into the corpus cavernosum. The injections can result in abulk of injected material being present in one or more portions of thecorpus cavernosum. When the magnetic condom magnet strip is positionedproximal to the site(s) of injection, the magnetic field can produceforces and torques on the magnetic particulate associated with thecells, biologics and drugs, so that the injected material remainspositioned as desired in the corpus cavernosum.

In some modes of practice the magnetic condom is manipulated in a way toenhance distribution and positioning of the injected magneticparticulates with associated cells, biologics, or drugs in the desiredtissue location(s) in the penis. For example, the condom can bepartially or fully rotated in place on the penis, causing direction ofthe magnetic field to change. The condom can be rotated clockwise (arrow58 a) and counterclockwise (arrow 58 b), moving the magnetic strip overthe dorsal side of the penis, from the left to right side, and back fromright to left. Optionally, the condom can be moved (e.g., slightly) in aproximal to distal (and reverse) direction as well. This movement of thecondom causes changes in the location of the magnetic field and resultsin the movement of magnetic particulates associated with the cells,biologics or drugs within the corpus cavernosum. This enhances thepenetration and distribution of the cells, biologics and drugs into thetissue of the corpus cavernosum, while still positionally maintainingthe material in this general area.

In some embodiments, a condom that includes an electromagnet made from acoil of wire is used in the system and the methods of the invention. Thecoil of wire can be in the form of a tightly wound helix which producesa solenoid effect, and the generated magnetic field affects positioningof the magnetic particulate-associated cells, biologics or drugs in thepenis. Exemplary coils that can be attached to the condom have a desiredheight and diameter for attachment to the condom.

Referring to FIG. 6, in another embodiment the condom includes one ormore small electromagnetic coils 61 associated with the sheath materialof the condom 60. Also shown is a power supply 62, such as a batterypack, that generates the electric current for magnetic field inductionfrom the coil. One or more coils can be associated with the condom in adesired arrangement; for example a condom can include electromagneticcoils around its entire circumference, or a part of the circumference.In some embodiments, the condom can include one or more strips ofelectromagnetic coils along its length. If the condom includes multipleelectromagnetic coils, all of the coils can be in electroniccommunication with each other so that current passes through all of thecoils with a single current. Alternatively, the individual coils, orgroups of coils can have separate connections so magnetic fields can begenerated at different locations in association with the surface of thecondom at different times. For example, in some modes of practice, amagnetic field for one of the coils positioned at a first location onthe condom is generated for a first period of time, and subsequently amagnetic field for a second coil is generated for a second period oftime, and so forth. The alternating magnetic fields may produce desiredpositioning of magnetic particulate-associated cells, biologics or drugswithin the penis. In some cases, the alternating magnetic fields resultin better penetration and distribution of the magneticparticulate-associated cells, biologics or drugs in the corpuscavernosum, while still maintaining this material within this tissue.

Referring to FIG. 7, in another embodiment the condom 70 includes a wire71 wrapped around the circumference of the condom 70 in a helicalconfiguration. Also shown is a power supply 72, such as a battery pack,that generates the electric current for magnetic field induction fromthe coil. The helical configuration can extend for all or a portion ofthe length of the condom. When an electric current passes through it,the coil generates a magnetic field around the circumference of thepenis. The condom can be constructed by wrapping a small gauge wirearound the condom using an adhesive to secure the wire to the sheathmaterial. The wire can be wrapped very tightly so there is no spacingbetween the wire along the helical turns, or can be wrapped so there isa desired amount of spacing (gap) between the wire.

A system that includes the magnetic field-providing condom canoptionally include one or more components that would facilitate orenhance use of the system. For example, the system could be provide witha lubricant to facilitate placement of the condom on the penis, ormovement of the condom when performing a method of the invention, suchas rotating the condom in a clockwise or counterclockwise directionaround the penis. A lubricant may be applied to the penis or condomprior to use, or the condom may come pre-coated with a lubricant. Thesystem can also optionally be provided with an agent that prevents ortreats bacterial infection, such as an anti-microbial. Theanti-microbial may come pre-coated on the condom, or may be a componentthat is applied prior to or after steps in the treatment process.

In another aspect, the system and methods of the invention include amagnetic field-generating penis ring. Referring to FIG. 8, the penisring 80 can be configured to surround the penis 81 and placed over aportion of its length during use. The ring can include one or morepermanent magnets, or an electromagnetic coil, going around all or aportion of the ring. The permanent magnets or electromagnetic coil canbe encased within a housing, such as one made from a plastic or rubbermaterial. After the therapeutic composition is injected into one or moredesired areas of the penis, the ring can be placed on the penis, or thering can be placed on the penis prior to injection. In some modes ofpractice, the ring can be moved along the shaft of the penis, back andforth, to promote desired positioning of the magneticparticulate-associated cells, biologics, or drugs within the tissue.Alternatively, or in combination with the movement along the shaft, thering can be spun around the penis in clockwise and/or counterclockwisedirections. Optionally, the penis ring 80 can be fastened to a belt 82on opposite sides of the ring, so the ring can be held in place around apatient such as by placing the belt below the patient's waist.

In another aspect, the system and methods of the invention include amagnetic field-generating urethral catheter. The catheter can be adaptedfor either male or female use. Some urethral catheters are referred toas “Foley catheters,” and catheters of these types can be modified toprovide a magnetic field for use in the system and methods of theinvention. Flexible materials that make the tubing of a urethralcatheter are commonly selected from silicone, latex, and polyvinylchloride (PVC). Normally, a urethral catheter tube is navigated throughthe urethra so urine can be drained from the bladder from the end of theurinary catheter located within the bladder. Urethral catheters alsotypically include an inflatable balloon that allows the end of thecatheter to be held in the bladder. A modified urethral catheter thatprovides a magnetic field, and which can be used in the system andmethods of the invention, can include one or more permanent magnets, oran electromagnetic coil. Other components, such as a balloon, which isnormally used in urine drainage processes, are optional components inthe modified catheter. Common sizes of urethral catheters range from 10French to 28 French (F) (1 F=0.33 mm), with sizes in the range of 12F-16 F being common for use in adult humans, and having an innerdiameter (lumen) in the range of about 1-3 mm.

A magnetic field-generating urethral catheter can be constructed byloading the inner diameter of the flexible tube of the catheter with oneor more permanent magnets, or an electromagnetic coil. The magnets orcoil may be present in the inner diameter along the entire length of thetube, or may be present along a portion of the length of the tube, ormore than one portion of the length of the tube.

An exemplary method using a magnetic catheter includes one or moreinjections of a treatment composition into the corpus cavernosum of thepenis. When the magnetic field-generating catheter is placed inside theurethra, the magnetic field affects positioning of cells, biologics anddrugs, so they are maintained in the desired area for treatment. In somemodes of practice, the catheter can be moved back and forth in theurethra to change the location of the magnetic field source, therebycausing movement of the particulates and associated cells, biologic, ordrugs in a proximal and distal manner.

A system and method utilizing a magnetic field-generating urinarycatheter can be particularly effective for the treatment of patientshaving undergone radical prostatectomy. For example, a magneticfield-generating urinary catheter can be used in conjunction withmagnetic particulates associated with prostaglandin E1 (PGE1),phentolamine, papaverine, Forskolin, or a combination of these drugs.

In some embodiments, the device is in the form of a pessary whichassociates or incorporates one or more permanent magnets, or anelectromagnet, with the structural material used to form the pessary.Pessaries are small medical devices which can be inserted into thevagina or the rectum, and which can be maintained in position at theselocations by the pelvic floor musculature. In some modes of practice, avaginally inserted pessary can be used to treat a condition such asuterine prolapse, stress urinary incontinence, cystocele, or rectocele,while at the same time providing a magnetic field which affectspositioning movement of the magnetic particulate-associated cells,biologics, or drugs which have been delivered to the pelvic tissue.Therefore, in some embodiments, the pessary can provide treatment basedon the structural support the architecture of the pessary provides,along with the magnetic field action it provides to promote positioningof the injected composition in the target pelvic tissue.

An exemplary system and method includes stem cells associated withmagnetic particulates, such as adipose-derived stem cells, and amagnetic-field generating intravaginal or intrarectal pessary. In somemodes of practice, the cell-containing composition is injected into atissue site, such as the levator ani and/or the urethral sphincter forthe treatment of stress urinary incontinence (SUI). The adipose-derivedstem cells can be promoted to differentiate into smooth muscle cells(SMC) following injection and positioning as affected by the vaginalpessary, for reconstruction of the smooth and skeletal muscles in thedefective pelvic floor and for urethral support.

In some modes of practice, magnetic microparticle-associated cells,biologics, or drugs can be placed on a wound healing scaffold and themovement of the cells, biologics, or can be controlled or positionallymaintained by one or more magnetic devices.

In some modes of practice, the system and methods of the invention areused to treat a fibroid, such as a uterine fibroid, or a cancerousgrowth in tissue of the pelvic area. Uterine fibroids are benign tumorsthat originate from the uterine myometrium (smooth muscle) and theaccompanying connective tissue of the uterus. Fibroids include uterineleiomyomas, fibromyomas, and fibromas. For instance, therapeuticcompositions can be injected into fibroids, or the uterine artery, andthe position of the microparticulate-associated cells, biologics, ordrugs can be controlled using a magnetic field providing device, such asa magnetic field-generating pessary. In addition, therapeuticcompositions can be injected into the prostate, intravenously, into oraround cancerous tumors, or at other desired target sites to facilitatehealing and treatment.

In some embodiments, the system and methods of the invention include adevice that is used for treating long-term diarrhea or fecalincontinence. Exemplary devices are configured for internal use, such asan artificial anal sphincter (artificial bowel sphincter; O'Brien, P.E., et al. (2000) Dis. Colon. Rectum 43:1213) and those configured forexternal use, such as an adhesive wafer for application to the analopening which includes a drainable pouch. Internal or external fecalincontinence devices can include one or more permanent magnets, or anelectromagnet, and can be used in conjunction with magnetic particulatesassociated with cells, biologics, or drugs, for the treatment of fecalincontinence.

In another embodiment, the invention provides a device that is designedto apply mechanical forces on the penis in order to enhance distributionof a therapeutic composition within tissue of the penis. The device canmanipulate the penis to move cells, or other therapeutic material,within the vascular spaces to locate materials of the treatmentcomposition to tissue in need of regeneration. The therapeuticcomposition can be one that includes the magneticmicroparticle-associated cells, biologics, or drugs. With reference toFIG. 9a , the device includes a platform 90 which contacts a surface ofthe penis, and a series of rollers (91 a, 91 b, 91 c, etc) arrangedperpendicular to the penis when placed on the device, and in a parallelplane as the platform 90. The device may be constructed with just oneroller, but multiple rollers (two, three, four, five or more rollers)may be used increase the amount of tissue being manipulated in order toenhance distribution of the therapeutic composition in the penis. Therollers, at one end, can be attached to a roller track 92 which includesa mechanical member such as a chain, rod, or pulley, which drivesmovement of the rollers.

With reference to FIG. 9b , the platform and a roller are arranged inopposition and configured so a penis 93 can positioned between theplatform 90 and the rollers 91 a, 91 b, and 91 c. The gap between thesurface of the platform and the rollers may be varied based onanatomical considerations, as well as the amount of pressure intended tobe exerted on the penis during the treatment method. The rollers can beconstructed using a soft material, such as a foam or fabric, thatcontacts and applies force to a surface of the penis but that preferablyavoids causing any tissue trauma. The roller is capable of moving in oneor more directions to compress tissue of the penis when it is beingmoved. In some modes of practice the rollers move back and forth for adistance in the range of less than a centimeter to multiple centimeters.The device can provide a gentle but effective rotational force on thedorsal surface of the penis to allow a therapeutic composition to movethrough the tissue from base to tip and back again in a controlledmanner. This will, in turn, allow the therapeutic composition to fillall of the spaces to give the cells an opportunity to take hold of thelocal tissue to advance regenerative opportunities.

The penis roller device can also function to elevate all or a portion ofthe penis. By elevating the penis, distribution of the therapeuticmaterial in the penis can be enhanced. According to one arrangement, andwith reference to FIG. 9c , the device includes a hinge 94 at theproximal end of the platform 90. The platform can be attached to theroller track 92, and the platform 90 can mechanically pivot on the hinge94, which elevates the distal end of the platform and the roller track,and elevates the distal end of the penis according to arrow 95 a. Theplatform can then be pivoted back to a horizontal position according toarrow 95 b. Elevation of the penis can be performed while the penis isbeing rolled, or can be performed independently of the penis beingrolled.

The penis roller device can also include a magnetic field-generatingmember that can provide a positioning effect to magneticparticular-associated cells, biologics, or drugs that are injected intothe penis. For example, permanent magnets or electromagnets can beincluded in one or more of the rollers, or the platform. A magneticfield can be provided during the steps of rolling and/or elevating thepenis to enhance the distribution and maintenance ofparticular-associated cells, biologics, or drugs in the penis.

What is claimed is:
 1. A system for the treatment of a pelvic disordercomprising: a composition including magnetic particulates, the magneticparticulates being either (i) physically associated with a cellpopulation (ii) or physically associated with a drug or a biologicagent, or both (i) and (ii), the composition configured to be injectedinto tissue of a penis, the magnetic particulates includingnanoparticles; and a device configured to be placed onto the penis, thedevice including a member configured to provide a magnetic field whichinfluences movement of the magnetic particulates and the associated cellpopulation, drug, or biologic agent within the tissue of the patient. 2.The system of claim 1, wherein the device includes a wire through whichelectrical current can flow and which can generate the magnetic field.3. The system of claim 1, wherein the device includes one or morepermanent magnets.
 4. The system of claim 1, wherein the device includesa male condom.
 5. The system of claim 4, wherein the male condomincludes a wire formed into at least one coil that is coupled to thecondom.
 6. The system of claim 4, wherein the male condom includes—awire wrapped around the condom in a helical or coiled configuration,wherein the wire is configured as an electromagnet to provide themagnetic field.
 7. The system of claim 4, wherein the male condomincludes one or more magnets or the condom is constructed from materialcomprising a magnetic compound.
 8. The system of claim 1, wherein thedevice includes a penis ring.
 9. The system of claim 1, furthercomprising: an injection device configured to inject the compositioninto the penis.
 10. The system of claim 9, wherein the injection deviceincludes a syringe configured to inject the composition into the tissueof the penis.
 11. The system of claim 1, wherein the compositionincludes stem cells.
 12. The system of claim 11, wherein the stem cellsinclude adipose tissue-derived stem cells.
 13. The system of claim 1,wherein the device includes a platform and a roller, wherein theplatform and the roller are arranged in opposition to each other,wherein the roller is configured to move in one or more directions tocompress tissue of the penis when disposed between the roller and theplatform.
 14. The system of claim 1, wherein the nanoparticles have asize in a range of 10 nm to 500 nm.
 15. A method for the treatment of apelvic disorder comprising: delivering a composition to tissue of apenis, the composition including magnetic particulates and cells, themagnetic particulates being incorporated into the cells, the magneticparticulates including nanoparticles, placing a device onto the penis;and generating a magnetic field using the device such that the magneticfield causes movement of the magnetic particulates within the penis. 16.The method of claim 15, wherein the nanoparticles have a size in a rangeof 10 nm to 500 nm.
 17. The method of claim 15, wherein the cellsinclude stem stems.
 18. The method of claim 15, wherein the compositionincludes Platelet Rich Plasma (PRP).
 19. The method of claim 15, whereinthe composition includes Platelet Poor Plasma (PPP).